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HIF-1 stabilization exerts anticancer effects in breast cancer cells in vitro and in vivo
- Source :
- Biochemical Pharmacology. 175:113922
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Tumor hypoxia and high activity of hypoxia-inducible factor-1 (HIF-1) correlate with adverse disease outcomes, malignancy, resistance to therapy and metastasis. Nonetheless, recent studies indicate that under certain circumstances, HIF-1 stabilization may exert protective effects and even decrease tumor cell aggressiveness. This study aimed to characterize the potential anticancer effect of molidustat (BAY 85-3934), the prolyl hydroxylase (PHD) inhibitor and HIF-1 stabilizator. We confirmed that molidustat stabilizes HIF-1α and induces the expression of vascular endothelial growth factor (VEGF) in MDA-MB-231 breast cancer cells, to a similar or even greater extent than hypoxia. Interestingly, decreased cell survival and colony formation capabilities, together with S/G2 cell cycle arrest, were observed after treatment with PHD inhibitor. Importantly, molidustat enhanced the effectiveness of the chemotherapeutic drug, gemcitabine, on cancer cells. Finally, the xenograft model revealed decreased tumor growth in vivo after molidustat treatment. Both in vitro and in vivo analysis showed no differences in the angiogenic potential of endothelial cells treated with tumor-conditioned media or vascularization of the MDA-MB-231 xenografts, respectively. In summary, molidustat treatment exhibits an inhibitory effect on breast cancer cell survival, self-renewal capacity and potentiates the efficacy of chemotherapeutic gemcitabine.
- Subjects :
- 0301 basic medicine
Angiogenesis
Antineoplastic Agents
Breast Neoplasms
Mice, SCID
medicine.disease_cause
Biochemistry
Metastasis
angiogenesis
Mice
Random Allocation
03 medical and health sciences
chemistry.chemical_compound
breast cancer
0302 clinical medicine
Mice, Inbred NOD
In vivo
Cell Line, Tumor
medicine
prolyl hydroxylase inhibitor
Animals
Humans
Pharmacology
Dose-Response Relationship, Drug
Tumor hypoxia
Protein Stability
business.industry
HIF-1
Triazoles
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
Xenograft Model Antitumor Assays
Gemcitabine
Vascular endothelial growth factor
tumorigenesis
030104 developmental biology
chemistry
030220 oncology & carcinogenesis
Cancer cell
Cancer research
Pyrazoles
Female
business
Carcinogenesis
medicine.drug
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 175
- Database :
- OpenAIRE
- Journal :
- Biochemical Pharmacology
- Accession number :
- edsair.doi.dedup.....0cc021e51469dd0e06175feac5e9f1ac